HSP90 (heat shock protein 90) is one of the most abundant cellular proteins. There are at least four HSP90 family members in the human genome: the stress-inducible HSP90 (HSP90α or HSP90AA1), the constitutive cytosolic HSP90β (HSP90AB1), the endoplasmic reticulum-localized GRP94 (HSP90B), and the mitochondrial TRAP1 [2]. HSP90 contains approximately 730 amino acids arranged as 3 major domains: an N-terminal ATP-binding domain, a central domain and a C-terminal dimerization domain. HSP90 acts primarily as molecular chaperone, promoting the folding and stabilization of many labile cellular proteins. In general, HSP90 acts in concert with the HSP70 chaperone machinery, and also recruits multiple co-chaperone proteins to regulate its activity. Over 100 HSP90 substrates (“client proteins”) have been described in the art. HSP90 constitutes ˜1-2% of total protein in normal cells and this concentration can double under stress conditions, reflecting its importance in maintaining cellular homeostasis.
HSP90 expression and activity is frequently upregulated in tumor cells and is particularly associated with poor prognosis in breast cancer. Furthermore, HSP90 in tumor cells appears to exist in a hyperactivated state with elevated ATPase activity which is highly sensitive to HSP90 inhibition, compared to the largely latent form found in normal cells. This hyperactivated state suggests that HSP90 inhibitors can selectively target tumor cells, with relatively low impact on normal tissues. Many HSP90 client proteins are involved in various aspects of tumor growth and progression. HSP90 promotes the folding and/or stabilization of many oncogenic proteins that confer autonomous growth on cells (eg, EGFR and ErbB2, B-Raf and steroid hormone receptors, and also regulates multiple proteins that promote tumor cell survival (eg, IGF-1 receptor, PDK1 and Akt, RIP, IκBand survivin. HSP90 can also promote aberrant cell cycle progression by stabilizing Cdk4, Cdk6 and cyclin D, Cdk2, and Plk1. Conversely, HSP90 inhibitors can downregulate the cell cycle checkpoint kinase Chk1 and sensitize tumors to various forms of chemotherapy. HSP90 inhibition can also blunt tumor angiogenesis, since hypoxia-inducible factor (HIF-1α) and the vascular endothelial growth factor (VEGF) receptor tyrosine kinases are HSP90 clients. The receptor tyrosine kinase Met, which stimulates cellular motility, migration and invasion, is also downregulated in response to HSP90 inhibition, both directly and via inhibition of HIF-1α. Apart from its role as a cellular chaperone, HSP90α has also been implicated in extracellular matrix degradation and tumor cell invasion, via activation (and possibly stabilization) of the matrix metalloproteinase MMP2. HSP90 depletion or inhibition promotes telomere erosion and apoptosis, and can also enable the evolution of heterogenous, metastatic and drug-resistant phenotypes by allowing propagation of metastable mutations. HSP90 has been implicated in activation of the unfolded protein response (UPR,). Failure of the UPR (for example, via inhibition of HSP90) leads to an ER stress signal and apoptosis. Therefore, HSP90 inhibitors can promote tumor cell death indirectly by disrupting the UPR, as well as by directly targeting pro-survival factors.
Accordingly, there is a need for new compounds that can inhibit HSP90.